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Title: Boosting of HIV envelope CD4 binding site antibodies with long variable heavy third complementarity determining region in the randomized double blind RV305 HIV-1 vaccine trial
Authors: David Easterhoff
M. Anthony Moody
Daniela Fera
Hao Cheng
Margaret Ackerman
Kevin Wiehe
Kevin O. Saunders
Justin Pollara
Nathan Vandergrift
Rob Parks
Jerome Kim
Nelson L. Michael
Robert J. O’Connell
Jean Louis Excler
Merlin L. Robb
Sandhya Vasan
Supachai Rerks-Ngarm
Jaranit Kaewkungwal
Punnee Pitisuttithum
Sorachai Nitayaphan
Faruk Sinangil
James Tartaglia
Sanjay Phogat
Thomas B. Kepler
S. Munir Alam
Hua Xin Liao
Guido Ferrari
Michael S. Seaman
David C. Montefiori
Georgia D. Tomaras
Stephen C. Harrison
Barton F. Haynes
Duke University
Children's Hospital Boston
Dartmouth College
Walter Reed Army Institute of Research
Armed Forces Research Institute of Medical Sciences, Thailand
Thailand Ministry of Public Health
Mahidol University
Sanofi Pasteur
Boston University
Harvard Medical School
International Vaccine Institute, Seoul
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Feb-2017
Citation: PLoS Pathogens. Vol.13, No.2 (2017)
Abstract: © 2017 Public Library of Science. All Rights Reserved. The canary pox vector and gp120 vaccine (ALVAC-HIV and AIDSVAX B/E gp120) in the RV144 HIV-1 vaccine trial conferred an estimated 31% vaccine efficacy. Although the vaccine Env AE.A244 gp120 is antigenic for the unmutated common ancestor of V1V2 broadly neutralizing antibody (bnAbs), no plasma bnAb activity was induced. The RV305 (NCT01435135) HIV-1 clinical trial was a placebo-controlled randomized double-blinded study that assessed the safety and efficacy of vaccine boosting on B cell repertoires. HIV-1-uninfected RV144 vaccine recipients were reimmunized 6–8 years later with AIDSVAX B/E gp120 alone, ALVAC-HIV alone, or a combination of ALVAC-HIV and AIDSVAX B/E gp120 in the RV305 trial. Env-specific post-RV144 and RV305 boost memory B cell VHmutation frequencies increased from 2.9% post-RV144 to 6.7% post-RV305. The vaccine was well tolerated with no adverse events reports. While post-boost plasma did not have bnAb activity, the vaccine boosts expanded a pool of envelope CD4 binding site (bs)-reactive memory B cells with long third heavy chain complementarity determining regions (HCDR3) whose germline precursors and affinity matured B cell clonal lineage members neutralized the HIV-1 CRF01 AE tier 2 (difficult to neutralize) primary isolate, CNE8. Electron microscopy of two of these antibodies bound with near-native gp140 trimers showed that they recognized an open conformation of the Env trimer. Although late boosting of RV144 vaccinees expanded a novel pool of neutralizing B cell clonal lineages, we hypothesize that boosts with stably closed trimers would be necessary to elicit antibodies with greater breadth of tier 2 HIV-1 strains. Trial Registration: NCT01435135
ISSN: 15537374
Appears in Collections:Scopus 2016-2017

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